Alternative titles; symbols
HGNC Approved Gene Symbol: CXCL8
Cytogenetic location: 4q13.3 Genomic coordinates (GRCh38): 4:73,740,569-73,743,716 (from NCBI)
Interleukin-8 (IL8) is a member of the CXC chemokine family These small basic heparin-binding proteins are proinflammatory and primarily mediate the activation and migration of neutrophils into tissue from peripheral blood (Hull et al., 2001).
Modi et al. (1989, 1990) cloned the IL8 gene.
Using CAT assays and 3-prime RACE, Yu and Chadee (2001) determined that the IL8 polyadenylation site is located at nucleotide 3152 of the 1,248-base 3-prime untranslated region (UTR). Reporter gene analysis showed that an AU-rich stretch, elements known to be involved in mRNA destabilization, in the 'e region' (nucleotides 2387 to 2743 of the genomic DNA) of the 3-prime UTR is essential for posttranscriptional suppression of IL8 gene expression.
Palter et al. (2001) characterized the IL8 system, which includes IL8, its receptors IL8RA (146929) and IL8RB (146928), and its degradative enzyme aminopeptidase N (151530), in the human fallopian tube by immunohistochemistry. IL8 was found in the human fallopian tube predominantly in the epithelial cells and was present in greater amounts in the distal compared with the proximal tube. IL8RA and IL8RB localized in the tube in similar patterns. Aminopeptidase N was found in tubal stromal tissue at the epithelial-stromal border and perivascularly. The authors concluded that the IL8 system may be an active component of tubal physiology and that aminopeptidase N may limit the systemic effects of epithelial IL8.
Modi et al. (1989, 1990) mapped the IL8 gene to 4q12-q21 by somatic cell hybridization and in situ hybridization. Modi et al. (1990) pointed out that this is the same chromosome location as that of 3 other members of the platelet factor-4 gene superfamily: platelet factor-4 (PF4; 173460), melanoma growth stimulatory activity (GRO1; 155730), and interferon-gamma-induced factor (SCYB10; 147310).
Radiation hybrid mapping had indicated that 11 genes encoding the CXC chemokine family, of which IL8 is a member, reside on chromosome 4q, spanning a region of approximately 2.75 Mb (Modi and Chen, 1998).
By PCR analysis and mapping of YAC clones, O'Donovan et al. (1999) localized a number of CXC chemokine genes to 4q12-q21. They proposed that the order in this region is centromere--IL8--GRO1/PPBP (121010)/PF4--SCYB5 (600324)/SCYB6 (138965)--GRO2 (139110)/GRO3 (139111)--SCYB11 (604852)--SCYB10--MIG (601704)--telomere. The IL8 gene was localized to 4q12-q13.
Chemokines are a group of small (approximately 8-14 kD), mostly basic, structurally related molecules that regulate cell trafficking of various types of leukocytes through interactions with a subset of 7-transmembrane, G protein-coupled receptors. Chemokines also play fundamental roles in the development, homeostasis, and function of the immune system, and they have effects on cells of the central nervous system as well as on endothelial cells involved in angiogenesis or angiostasis. Chemokines are divided into 2 major subfamilies, CXC and CC, based on the arrangement of the first 2 of the 4 conserved cysteine residues; the 2 cysteines are separated by a single amino acid in CXC chemokines and are adjacent in CC chemokines. CXC chemokines are further subdivided into ELR and non-ELR types based on the presence or absence of a glu-leu-arg sequence adjacent and N terminal to the CXC motif (summary by Strieter et al., 1995; Zlotnik and Yoshie, 2000).
Baggiolini et al. (1989) reviewed the evidence concerning the role of IL8 in disease.
In a Japanese population, Emi et al. (1999) demonstrated an association between a specific allele at the IL8 locus and diffuse panbronchiolitis (604809), a distinctive chronic inflammatory lung disease found predominantly in Asian populations.
IL8 has been implicated in the pathogenesis of the viral lower respiratory tract infection bronchiolitis, caused by the respiratory syncytial virus (RSV). This disease is responsible for major epidemics each year, with many thousands of infants requiring hospital treatment. High levels of IL8 are found in nasal secretions and tracheal aspirates of infants with RSV bronchiolitis, and the level of IL8 appears to be correlated with disease severity (Smyth et al., 2000).
Bruun et al. (2001) investigated whether IL8 is produced in human adipose tissue in vitro. In adipose tissue fragments, interleukin 1-beta (IL1B; 147720) (3 nM) and tumor necrosis factor-alpha (TNFA; 191160) (0.6 nM) were able to stimulate IL8 production by 12-fold and 5-fold, respectively, when incubated for 48 hours. Incubations with isolated adipocytes were performed up to 6 hours, and IL1B and TNFA significantly increased IL8 production by 50 to 60%. Dexamethasone (50 nM) decreased IL8 production from adipose tissue fragments by 57% and from adipocytes by 37%. Thus, the effect of proinflammatory cytokines and dexamethasone on IL8 production in adipose tissue seems to be mediated at the transcriptional level. The authors concluded that IL8 is produced and released from human adipose tissue and from isolated adipocytes in vitro, which may indicate that IL8 from adipose tissue could be involved in some obesity-related complications.
IL8 induces rapid mobilization of hematopoietic progenitor cells (HPCs). Mobilization can be prevented completely in mice by pretreatment with neutralizing antibodies against the beta-2-integrin Lfa1 (CD11A; 153370). In addition, murine HPCs do not express Lfa1, indicating that mobilization requires a population of accessory cells. Pruijt et al. (2002) showed that polymorphonuclear cells (PMNs) serve as key regulators in IL8-induced HPC mobilization. The role of PMNs was studied in mice rendered neutropenic by administration of a single dose of antineutrophil antibodies. Absolute neutropenia was observed up to 3 to 5 days, with a rebound neutrophilia at day 7. The Il8-induced mobilizing capacity was reduced significantly during the neutropenic phase, reappeared with recurrence of the PMNs, and was increased proportionately during the neutrophilic phase. The data demonstrated that IL8-induced mobilization of HPCs requires the in vivo activation of circulating PMNs.
Cystic fibrosis (CF; 219700), which is caused by mutation in the CFTR gene (602421), is characterized by severe lung inflammation. The inflammatory process is believed to be caused by massive overproduction of the proinflammatory protein IL8, and the high levels of IL8 in the CF lung are therefore believed to be the central mechanism behind CF lung pathophysiology. Srivastava et al. (2004) showed that digitoxin, at sub-nM concentrations, can suppress hypersecretion of IL8 from cultured CF lung epithelial cells. Certain other cardiac glycosides were also active but with much less potency. The specific mechanism of digitoxin action is to block phosphorylation of the inhibitor of nuclear factor kappa-B (see 164011). This phosphorylation is a required step in the activation of the NF-kappa-B (see 164011) signaling pathway and the subsequent expression of IL8. Digitoxin also has effects on global gene expression in CF cells. Srivastava et al. (2004) found that of the informative genes expressed by a CF epithelial cell line, 58 were significantly affected by gene therapy with wildtype CFTR. Of these 58 genes, 36 (62%) were similarly affected by digitoxin and related active analogs. They interpreted this result as suggesting that digitoxin can also partially mimic the genomic consequences of gene therapy with CFTR. Srivastava et al. (2004) suggested that digitoxin, with its long history of human use, should be considered as a candidate drug for suppressing IL8-dependent lung inflammation in CF.
Schistosoma species (see 181460) are helminth parasites that are adept at manipulating the host immune system to allow tolerance of chronic worm infections without overt morbidity. This modulation of immunity by schistosomes prevents a range of immune-mediated diseases, including allergies and autoimmunity. Smith et al. (2005) identified a molecule produced by Schistosoma eggs, termed S. mansoni chemokine-binding protein (smCKBP), that bound several chemokines, including CXCL8. SmCKBP blocked interaction of these chemokines with their receptors and thereby inhibited induction of inflammation. Smith et al. (2005) proposed that since smCKBP is unrelated to host proteins, it may have potential as an antiinflammatory agent.
Polesskaya et al. (2016) found that the deadenylase CNOT6L (618069) had an inhibitor role in human muscle cell differentiation, independently of a modification of the myoblast growth rate. Transcriptomic analysis of CNOT6L-knockdown immortalized human LHCN myoblasts identified target mRNAs of CNOT6L, with the IL8 as the most upregulated gene in knockdown cells. Analyses showed that IL8 modulated myoblast differentiation and was a direct functional target of CNOT6L deadenylase. CNOT6L bound to IL8 mRNA in differentiating skeletal myoblasts and destabilized the mRNA, most likely by initially shortening its poly(A) tail, resulting in modulation of IL8 protein expression and thereby influencing differentiation of LHCN myoblasts.
Using cryoelectron microscopy, Liu et al. (2020) determined the structure of human IL8-activated CXCR2 in complex with inhibitory G protein (Gi; see 139310). They also reported the crystal structure of CXCR2 bound to an allosteric antagonist. The results revealed a unique shallow mode of binding between CXCL8 and CXCR2 and also showed the interactions between CXCR2 and Gi. Further structural analysis of CXCR2 inactive and active states revealed a distinct activation process and competitive small-molecule antagonism of chemokine receptors.
Hull et al. (2000) found that a common single-nucleotide polymorphism (SNP) at position -251 in the promoter region of IL8 is associated with susceptibility to severe disease after infection with RSV, raising the possibility that the susceptibility to bronchiolitis is a consequence of increased IL8 production after RSV infection. Hull et al. (2001) reported data from a different set of families which replicated this finding. Combined analysis of 194 nuclear families through use of the transmission/disequilibrium test gave P = 0.001. To explore the underlying genetic cause, they identified 9 SNPs in a 7.6-kb segment spanning the IL8 gene and its promoter region and used 6 of these to define the haplotypic structure of the IL8 locus. The -251A allele of IL8 was found to reside on 2 haplotypes, only 1 of which was associated with disease, suggesting that this may not be the functional allele. Studies in Europeans and Africans indicated that marked haplotype-frequency differences cannot be due to neutral equilibrium and that selective pressure may have acted on this locus.
Hull et al. (2004) stated that viral bronchiolitis is the commonest cause of infant admissions to hospital in the industrialized world (Allport et al., 1997). RSV is highly infectious, and most children are infected before the end of their second winter. It is not clear what proportion of otherwise healthy children develop bronchiolitis after infection with RSV; most suffer only mild cold-like symptoms. Hull et al. (2004) mapped the genomic boundaries of the disease association with polymorphism at the IL8 locus by case-control analysis and transmission/disequilibrium test (TDT) in 580 affected UK infants. They excluded adjacent chemokine genes as the cause of the association, and identified a disease-associated haplotype that spans a 250-kb region from AFM (104145) to IL8. Between these 2 genes they identified only 1 gene of possible interest, RASSF6 (612620), which encodes a Ras effector protein.
Eumycetoma is a tumorous fungal infection, typically of the hands or feet, characterized by the infiltration of large numbers of neutrophils. It is caused by Madurella mycetomatis, a pathogen that is abundant in the soil and on the vegetation of Sudan, where the disease is common. Van de Sande et al. (2007) noted that ELISA has shown near universal IgG seropositivity in mycetoma patients and controls from endemic areas, but no seropositivity in European controls, implying that most individuals in endemic areas are exposed to the pathogen, but only a small percentage develop disease. Van de Sande et al. (2007) studied 11 SNPs in genes involved in neutrophil function in 125 Sudanese mycetoma patients and 140 ethnically and geographically matched controls and found significant differences in allele distributions for SNPs in IL8, IL8RB, TSP4 (THBS4; 600715), NOS2 (163730), and CR1 (120620). Serum IL8 was significantly higher in patients compared with controls, while nitrite/nitrate levels were lower in patients and seemed to be associated with delayed wound healing. Van de Sande et al. (2007) concluded that there is a genetic predisposition toward susceptibility to mycetoma.
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